Introduction
Glioblastoma (GBM) is the most fatal brain tumor in adults. Current survival rates of GBM remain below 2 years due to GBM’s aggressive cellular migration and genetically driven treatment ...escape pathways. Despite our rapidly increasing understanding of GBM biology, earlier diagnoses, and refined surgical techniques, only moderate survival benefits have been achieved. Nonetheless, the pressing need for better survival rates has brought forward a multitude of newer therapeutic approaches and opened the door for potential personalization of these modalities in the near future.
Methods
We reviewed the published literature discussing the current state of knowledge regarding GBM biology and therapy and summarized the information that may point toward future personalized therapeutic strategies.
Results
Several novel modalities such as oncolytic viruses, targeted immune, and molecular therapies, and tumor treating fields have been introduced. To date, there is no single treatment modality for GBM, but rather a wide spectrum of combined modalities that address intratumoral cellular and genetic variabilities. While the current state of GBM research and clinical trial landscape may hold promise, current literature lacks any fruitful progress towards personalized GBM therapy.
Conclusion
In this review, we are discussing our recent knowledge of the GBM genetic biologic landscape and the current advances in therapy, as well as providing a blueprint for an envisioned GBM management paradigm that should be personalized and adaptable to accommodate each patient’s diverse genetic variations and therapy response/escape patterns.
The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating ...such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 sFormula: see text) and moderate (14 sFormula: see text) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.
Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the ...pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.
Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity ...compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders-80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.
The endogenous production of highly reactive oxidation species is an inherent by-product of cellular energy metabolism. Cellular antioxidant defense systems (AODS) comprising various antioxidants ...counter these damaging effects. Several lines of evidence, including postmortem studies, suggest increased oxidative stress in patients with schizophrenia. Some genetic association studies and gene-expression studies suggest that patients also may have altered ability to mount antioxidative mechanisms. As the genetic associations may provide etiologic evidence in support of the oxidative-stress hypothesis of schizophrenia, a focused review has been conducted. We also suggest avenues for further research.
Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing ...central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/β, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.
Basic science investigations have consistently shown that repeated exposure to psychostimulant drugs, such as cocaine, activate the immune response and lead to inflammatory changes in the brain. No ...previous in vivo studies have confirmed this observation in chronic cocaine-abusing humans. To test this hypothesis, we used positron emission tomography imaging to measure the binding of (11)CPBR28 to the 18 kDa translocator protein (TSPO), a marker for microglial activation in a group of 15 recently abstinent cocaine abusers and 17 matched healthy controls. (11)CPBR28 volumes of distribution expressed relative to total plasma ligand concentration (VT) were measured in subjects with kinetic analysis using the arterial input function. Subjects were also genotyped for the TSPO alanine147 threonine (Ala147Thr, rs6971) polymorphism that has been shown to influence the in vivo binding of PBR28 to TSPO. Consistent with previous reports, the TSPO Ala147Thr genotype predicted the in vivo binding of (11)CPBR28. No significant differences in (11)CPBR28 VT were observed in the cortical and subcortical regions in cocaine abusers compared with healthy controls. The results of this in vivo study do not support increased TSPO expression and, by extension, microglial activation in chronic cocaine-abusing humans. Further research with more direct markers of microglial activation is necessary to conclusively rule out neuroinflammation in cocaine dependence.
Glioblastoma (GBM) is fatal and the study of therapeutic resistance, disease progression, and drug discovery in GBM or glioma stem cells is often hindered by limited resources. This limitation slows ...down progress in both drug discovery and patient survival. Here we present a genetically engineered human cerebral organoid model with a cancer-like phenotype that could provide a basis for GBM-like models. Specifically, we engineered a doxycycline-inducible vector encoding shRNAs enabling depletion of the TP53, PTEN, and NF1 tumor suppressors in human cerebral organoids. Designated as inducible short hairpin-TP53-PTEN-NF1 (ish-TPN), doxycycline treatment resulted in human cancer-like cerebral organoids that effaced the entire organoid cytoarchitecture, while uninduced ish-TPN cerebral organoids recapitulated the normal cytoarchitecture of the brain. Transcriptomic analysis revealed a proneural GBM subtype. This proof-of-concept study offers a valuable resource for directly investigating the emergence and progression of gliomas within the context of specific genetic alterations in normal cerebral organoids.
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